The present invention, in some embodiments thereof, relates to a method of preventing secondary infections in subjects infected with a pathogen using agents that down-regulate extracellular matrix remodeling.
Viral pandemics, such as influenza have caused millions of deaths worldwide. An extreme example is the 1918 pandemic which spread to six continents and infected ˜500 million people reaching death toll of 50 million. Investigation of clinical cases and autopsy samples indicated that more than 95% of case fatalities were complicated by secondary bacterial infections, most commonly Streptococcus pneumoniae (S. pneumoniae). Immune cells recruited to the site of infection are critical for influenza clearance. However, growing evidence shows that infiltrating immune cells can also generate excessive inflammatory responses resulting in collateral tissue damage and disruption of the blood-air-barrier.
Tissue tolerance to pathogens is an important evolutionary trade-off, balancing the host immune response to pathogens while maintaining tissue function. However, tolerance capacity differs between various organs; lungs have a relatively low tissue tolerance capacity, and are more vulnerable to tissue damage. Accordingly, it has been argued that during respiratory viral infections uncontrolled host-derived immune responses, rather than viral titers, may be the leading cause of death. These responses are primarily associated with inflammatory monocytes, granulocytes, macrophages and dendritic cells. Accordingly, influenza-infected lungs are diffusely hemorrhagic, potentially linking the host response with tissue destruction. Tissue breaching may prime secondary bacterial invasion coupled with tissue disruption and, in extreme cases, may result in death. The interaction between influenza and secondary bacterial infections has long been studied, yet the molecular mechanisms by which influenza infection primes the tissue to secondary infections are not fully understood.
One of the host's tolerance components is the integrity of respiratory epithelial barriers anchored to the extracellular matrix (ECM). The ECM scaffold is produced by the cells in the tissue and is composed of two layers: I) the interstitial matrix, a three-dimensional gel of polysaccharides and fibrous proteins, and II) the basement membrane, a mesh-like sheet formed at the base of epithelial tissues. ECM turnover is regulated by multiple proteolytic enzymes including matrix metalloproteinases (MMPs) that are responsible for the irreversible cleavage of a plethora of ECM molecules under normal and pathological conditions. Dysregulated proteolytic activity is often associated with inflammation, cancer, and infectious diseases. Accordingly, studies in pathological conditions have shown that dysregulated proteolysis of ECM molecules and related protein fibers have significant effects on tissue function. Specifically, MMPs were shown to play critical roles in lung organogenesis and many MMPs are involved in the acute and chronic phases of lung inflammatory diseases (Greenlee et al., 2007, Physiological reviews 87, 69-98). Several substrates of MMPs have been identified during lung development, including ECM scaffold proteins, cell adhesion molecules, growth factors, cytokines, and chemokines (Greenlee et al., 2007, Physiological reviews 87, 69-98).
Membrane type-I matrix metalloproteinase (MT1-MMP/MMP-14), a membrane tethered collagenase, is a key regulator in development and homeostasis of the lung as well as mediating wound healing, airway remodeling, and cell trafficking. Accordingly, it is expressed by multiple cell populations in the respiratory tract, including fibroblasts, endothelial cells and macrophages (Greenlee et al., 2007, Physiological reviews 87, 69-98). The functions of macrophage-derived proteases during inflammation are typically associated with tissue invasion or degradative events. In macrophages MT1-MMP serves not only as a protease acting on the ECM, but also regulates macrophage immune response. Recruited monocytes and macrophages up-regulate a broad spectrum of ECM remodelers including various MMPs. Depending on the conditions, macrophages express a spectrum of MMPs and their inhibitors: these have been associated with both physiological and pathological lung remodeling events. MMP-9 (gelatinase B) was shown to be beneficial for recovery from influenza infection by promoting migration of neutrophils to the infection site (Bradley et al., 2012, PLoS pathogens 8, e1002641). Despite these important findings, a systematic analysis of ECM proteolytic pathways during respiratory infections, including the trade-off between ECM integrity and immune protection, has never been completed.
Background art includes Cheung et al., Cardiovasc Pathol. 2006 March-April; 15(2):63-74, Elkington et al., 2005 British Society for Immunology, Clinical and Experimental Immunology, 142:12-20; Devy et al., Biochemistry Research International, Volume 2011, Article ID 191670, doi:10.1155/2011/191670; Renckens et al., J Immunol 2006; 176:3735-3741; Vanlaere et al., Clinical Microbiology Reviews, April 2009, Vol 22, p. 224-239 and Udi et al., 2015, Structure 23, 1-12, Jan. 6, 2015.